The present invention relates to a composition and process of forming chemical bonds, such as carbon-carbon and carbon-heteroatom bonds. The present invention has particular applicability to the formation of chemical bonds by transmetallation reaction chemistry.
Over the past several decades, palladium (Pd) catalyzed carbon-carbon bond formation reactions have been extensively studied and widely applied in organic synthesis [Tsuji, J. Transition Metal Reagents and Catalysis, John Wiley: Chichester, 2000]. The ultimately formed chemical bonds are produced by a sequence of intermediates. These include the formation of an aryl or alkenylpalladium halide complex generated by oxidative addition of the aryl or alkenylhalide with Pd. These complexes can, in turn, undergo transmetallation with many reagents. This reaction sequence is followed by reductive elimination to form a carbon-carbon bond and to regenerate a Pd (0) species. This system provide a methods for developing many crosscoupling reactions. The following authors are known to employ the element in the parentheticals for coupling reactions: Suzuki (boron, B), Stille (tin, Sn), Negeshi (zinc and aluminum, Zn and Al), Kumada (magnesium, Mg) [Miyaura, N.; Suzuki. A. Chem. Rev. 1995, 95, 2457; Knight, D. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Pergamon Press: Oxford, 1991, Vol 3, Chapter 2.3; Suzuki, A. Pure Appl. Chem. 1985, 57, 1749; Tamao, K.; Kumada, M. in The Chemistry of the Metal-Carbon Bond (Ed., F. R. Hartley), Vol. 4, Wiley, N.Y., 1987, Chapter 9 p 819; Suzuki, A. Pure Appl. Chem. 1985, 57, 1749; Stille, J. K. Angew Chem. Int. Ed. Engl. 1986, 25, 508; Negishi, E. Acc. Chem. Res. 1982, 15, 340. (i) Kumada, M. Pure Appl. Chem. 1980, 52, 669].
In contrast, palladium-catalyzed homocoupling reactions have not been studied extensively, although some homocoupling reactions of aryl and alkenyl halides facilitated by a Pd species are known. [See, e.g., Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett. 1999, 1, 1205; Hassan, J.; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron 1998, 54, 13793; Jutand, A.; Mosleh, A. J. Org. Chem. 1997, 62, 261; Smith, K. A.; Campi, E. M.; Jackson, W. R.; Marcuccio, S.; Naeslund, C. G. M.; Deacon, G. B. Synlett, 1997, 131; Jutand, A.; Mosleh, A. Synlett, 1993, 568; Jutand, A.; Negri, S.; Mosleh, A. Chem. Commun., 1992, 1792; Miura, M.; Hashimnoto, H.; Itoh, K.; Nomura, M. Chem. Lett. 1990, 459]. Other known coupling reactions include Glazer coupling (Chem Ber 1869, 2, 422, Cadiot P, Chodkiewwicz, W. Chemistry of Acetylenes, 1969, Marcel Dekker, New York, p 597), Ullman-type Coupling reactions (Semmelhack, M. F.; Helwuist, P. M.; Jones, L. D. J. Am. Chem. Soc. 1971, 93 5908; Kende, A.; Liebeskind, L. S. Braitsch, D. M. Tetrahdedron Lett. 1975, 3375; Prerce, V.; Bae, J. Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1994, 60, 176). For forming carbon-heteroatom bonds, Hartwig and Buchwald have made a couple of catalysts. Hartwig, J. F. Angew Chem. Int. Ed. Engl. 1998, 37, 2047; Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1133; Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413).
The following table summarizes coupling reactions. 
Although the above mentioned metal-catalyzed and metal-facilitated carbon-carbon and carbon-heteroatom bond formation reactions are useful for organic synthesis, they are also limited. For example, an Ullman coupling reaction generally is carried out under harsh conditions and many hindered or aryl halides having one or more electron donating groups resist coupling. Glaser coupling requires the presence of oxygen, which can destroy many sensitive products, particularly diynes. A number of alkynes with functional groups do not undergo coupling in a Glaser coupling reaction. Moreover, the coupling reaction is generally not applicable to polymerization or oligomerization reactions.
The synthesis of diynes is particularly problematic as diynes are not stable and prone to decomposition. Therefore, only alkyl halides, aryl halides (e.g., RI or RBr) that react under mild conditions will couple. In Sonogashira, Suzuki, Stille, Negishi, Kumada, Hartwig-Buchwald coupling reactions, oxidative addition of aryl halides can be a difficult step. This is particularly true if the aryl halide has two groups substituted in adjacent positions. To minimize or avoid the oxidative addition of these difficult substrates would be of great interest in organic synthesis. For a Suzuki coupling reaction, a known side reaction product is dehalogenation reaction. In Sonogashira, Suzuki, Stille, Negishi, Kumada, Hartwig-Buchwald coupling reactions, the oxidative addition of RX when R is a simple alkyl group with a xcex2-hydrogen is a slow process and metal compounds can easily form undesirable xcex2-hydrogen elimination products. This has been a major limitation of these coupling reactions.
Hence, there is a need for metal-catalyzed catalytic reactions which can improve coupling reactions, or, ideally, overcome many of the limitation of prior art processes. There is also a need in the chemical industry for making existing pharmaceutical products, agrochemical products, polymers products and as well as new products by a facile chemical bond forming reaction.
An advantage of the present invention is a composition for chemical bond formation.
An additional advantage of the present invention is a method of forming chemical bonds by transmetallation.
Additional advantages, and other features of the present invention will be set forth in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from the practice of the present disclosure. The advantages may be realized and obtained as particularly pointed out in the appended claims.
According to the present invention, the foregoing and other advantages are achieved in part by a composition comprising at least one xcex1-halo carbonyl compound; and one or more transmetallation reagents.
Embodiments include, compositions having a base, e.g. a compound having an available pair of electrons. The forgoing bases include triethyl amine (Et3N), DABCO, Et2NH, NaORb, Na2CO3, KF, K3PO4, NaOAc, KOH, and RbNX, where Rb is one or more of an H, alkyl groups and X is an anion, such as a halogen or ester. The composition includes at least one transmetallation reagent. This reagent can be prepare prior to forming the composition or in situ.
Transmetallation reagents are formed by the addition of a metal or metal catalyst to a target compound. The target compound is the compound undergoing chemical bond formation. For example, transmetallation reagents include metal complexes, such as RM, RB(OH)2, RBRxe2x80x22, RSnRxe2x80x23, RZnX, RHgX, RMgR, RSiRxe2x80x23, RCu, ROM, RNHM, RAlRxe2x80x22, wherein R and Rxe2x80x2 are independently an aryl or alkyl group and M is a metal. Other organometallic species are also contemplated. Additionally, an xcex1-halo carbonyl species which can easily undergo oxidative addition with redox active metals is included in this composition for coupling reactions.
Another aspect of the present invention is forming chemical bonds. Bond formation can advantageously be carried out in both intermolecular reactions (i.e. between two or more target compounds), or intramolecular (within the same target compound) reactions. Chemical bond formation methods can be used to make biologically active compounds or polymers, such as SP-carbon type of molecules. The method comprises combining at least one transmetallation reagent comprising a target compound with at least one xcex1-halo carbonyl compound; and forming a bond to or within the target compound of the transmetallation reagent.
In another aspect of the invention, a process for hydroboration and asymmetric hydroboration of boric compounds and coupling of bisboronic compounds by either intramolecular or intermolecular coupling is contemplated. The process comprises: combining at least one xcex1-halo carbonyl compound with at least one transmetallation reagent comprising a boric compound; and coupling the boric compound.
Additional advantages of the present invention will become readily apparent to those skilled in this art from the following detailed description, wherein only the preferred embodiments of the present invention are shown and described, simply by way of illustration but not limitation. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modification in various obvious respects, all without departing from the spirit of the present invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
The present invention relates to a composition and process of forming chemical bonds, such as carbon-carbon and carbon-heteroatom bonds. The present invention has particular applicability to the formation of chemical bonds by transmetallation reaction chemistry.
In an embodiment of practicing the present invention, at least one xcex1-halo carbonyl compound, e.g. an xcex1-bromo carbonyl compound, is combined with at least one transmetallation reagent comprising a target compound; and forming a chemical bond to or within the target compound. Bond formation can advantageously be carried out in both intermolecular reactions (i.e. between two or more target compounds, such as in coupling reactions), or intramolecular (i.e. within the same target compound, such as an oxidation reaction) reactions.
In one aspect of the practicing the method a base is also combined with the transmetallation reagent and xcex1-halo carbonyl compound. Useful bases in transmetallation chemistry are known and include triethyl amine (Et3N), DABCO, Et2NH, NaORb, Na2CO3, KF, K3PO4, NaOAc, KOH, and RbNX, where Rb is one or more of an H, alkyl groups and X is an anion, such as a halogen or ester.
It is contemplated that the transmetallation reagent can be prepare prior to the intended bond forming reaction or in situ. The transmetallation reagents can be formed by the addition of a metal or metal catalyst to a target compound. The target compound is the compound undergoing chemical bond formation. The transmetallation reagent can include one or more elements consisting of B, Sn, Al, Zn, Mg, Zr, Cu, Hg, and Si or organometalic species. For example, transmetallation reagents include metal complexes, such as RM, RB(OH)2, RBRxe2x80x22, RSnRxe2x80x23, RZnX, RHgX, RMgR, RSiRxe2x80x23, RCu, ROM, RNHM, RAlRxe2x80x22, where R and Rxe2x80x2 are the target compounds and wherein R and Rxe2x80x2 are independently an aryl or alkyl group and M is a metal. Other organometallic species are also contemplated. Additionally, an xcex1-halo carbonyl species which can easily undergo oxidative addition with redox active metals is included in this composition for coupling reactions.
The transmetallation reagents can be formed by adding a target compound to a catalyst or catalyst complex. These are known in the art and include transition metal catalysts, such as Pd(0), Ni(0), Rh(I), Pt(0), Ir(0), Cu(I), Mo(0), Mo(II), and Ru(II) catalysts with or without ligands as known in the art.
The catalyst can be selected from the group consisting of PtCl2; H2PtCl4; Pd2(DBA)3; Pd(OAc)2; PdCl2(RCN)2; PdCl2(diphosphine); [Pd(allyl)Cl]2; Pd(PR3)4; [Rh(NBD)2]X; [Rh (NBD)Cl]2; [Rh(COD)Cl]2; [Rh(COD)2]X; Rh(acac)(CO)2; Rh(ethylene)2(acac); [Rh(ethylene)2Cl]2; RhCl(PPh3)3; Rh(CO)2Cl2; RuHX(L)2; RuX2(L)2; Ru(arene)X2(diphosphine); Ru(aryl group)X2; Ru(RCOO)2(diphosphine); Ru(methallyl)2(diphosphine); Ru(aryl group)X2(PPh3)3; Ru(COD)(COT); Ru(COD)(COT)X; RuX2(cymen); Ru(COD)n; Ru(aryl group)X2(diphosphine); RuCl2(COD); (Ru(COD)2)X; RuX2(diphosphine); RuCl2(xe2x95x90CHR)(PRxe2x80x23)2; Ru(ArH)Cl2; Ru(COD)(methallyl)2; (Ir (NBD)2Cl)2; (Ir(NBD)2)X; (Ir(COD)2Cl)2; (Ir(COD)2)X; CuX (NCCH3)4; Cu(OTf); Cu(OTf)2; Cu(Ar)X; CuX; Ni(acac)2; NiX2; (Ni(allyl)X)2; Ni(COD)2; NiCl2(diphosphine); MoO2(acac)2; wherein each R and Rxe2x80x2 is independently selected from the group consisting of: alkyl or aryl; Ar is an aryl group; and X is a counteranion such as I, Br, Cl, OTf, BF4, SbF6, BAr4; and L represents a ligand.
Diphosphine include dppe, dppp, dppb, dppf, rac-Binap, chiral bisphosphines, DuPhos, BINAP, BPPM, DIPAMP, DIOP, MCCPM, BCPM, BICP, PennPhos, BPE, ChiraPhos, NorPhos, Degphos, BPPFA, JosiPhos, TRAP, TolBINAP, H8-BINAP, BINAPO, MOP, BINAPHOS, BIPHEMP, SEGPHOS, TUNAPHOS, KetalPhos, f-KetalPhos, HydroPhos, f-HydroPhos, Binaphane, f-Binaphane, FAP; and the mono phosphine includes: PPh3, P(o-tolyl)3, tri(2,6-dimethylphenyl)phosphine, PtBu3, PCy3, P(2-Furyl)3 and PPh2(o-ArC6H4).
In practicing an embodiment of the invention a transmetallation reagent is combined with at least one xcex1-halo carbonyl compound. Through a metal-enolate intermediate, the same or different transmetallation reagents can be transferred to a metal center and reductive elimination gives the desired product. These reactions can advantageously be carried out to form both intermolecular and/or intramolecular bonds. The method can be used to make biologically active compounds or polymers, such as SP-carbon type formation of molecules. An example of a metal mediated crosscoupling reaction is provided below. 
Double transmetallation through metal-enolates is also contemplated as an aspect of the present invention. In one aspect, the present invention relates to transition metal complexes with phosphine ligands as catalysts and an xcex1-halocarbonyl compound as a reagent for oxidative addition. The transmetallation reagents can be (Rxe2x80x94M) where R is an alkyl or aryl group, M contains B, Al, Sn, Zn, Mg, Si, Li, Cu, Hg, Zr, with or without other elements. Sometimes, substrates for the ligand exchanging reaction are ROH, RNH2, RN(Rxe2x80x2)H, RSH, CN and R2P(O)H. The transition metal complexes are useful as catalysts in homocoupling reaction, intramolecular cross-coupling reactions and other transformations.
Scheme 1 illustrates possible mechanisms of a Pd-catalyzed crosscoupling and homocoupling reactions. In the palladium-catalyzed crosscoupling reaction, the reaction is initiated by oxidative addition of R1xe2x80x94X to Pd, followed by transmetallation of R2xe2x80x94M, and reductive elimination of R1 and R2 gives the coupling product (R1-R2) (Scheme 1, path A). If the reductive elimination of R1 and R2 is slow, Pd(R2)2 can be generated and Pdxe2x80x94R1 can be transmetallated again with another R2xe2x80x94M (double transmetallation). Reductive elimination of Pd(R2)2 leads to a homocoupling product (Scheme 1, path B). It is believed that there is no report of the intermediate (I), derived from oxidative addition of R1X to a Pd (0) species, undergoing double transmetallation with R2xe2x80x94M to form an intermediate (III). Although not completely understood, the second transmetallation, i.e., replacing the R1 group with R2 in the intermediate II, may be an aspect in a palladium-catalyzed homocoupling reaction. In this example, the target compound R2 undergoes chemical bond formation with itself by a homocoupling reaction. 
Recently, considerable attention has been devoted to the palladium enolate chemistry [Wang, Z.; Zhang, Z. Lu, X. Organometallics 2000, 19, 775; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473; xc3x85hman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918; Sodeoka, M.; Shibasaki, M. Pure Appl. Chem. 1998, 70, 411 ] Several palladium enolate complexes have been well-characterized.
It is believed that the first transmetallation of an organoboron reagent to a palladium enolate was not reported or recognized previously. Through investigation and experimentation, it was demonstrated that an enolate anion can serve as a leaving group similar to a bromide or iodide in a transmetallation process. Since oxidative addition of readily available a-bromocarbonyl compounds to a palladium (0) species can also readily occur, double transmetallation can be carried out. This double transmetallation reaction is depicted below. Here, an alpha-bromo phenyl carbonyl compound give a Pd(II)Br(enolate) intermediate (I), double transmetallation with aryl boronic acids yields an intermediate(III), which leads to a homocoupling product through reductive elimination. 
As an example of this type of intramolecular bond formation, methyl xcex1-bromophenyl acetate ester 1 (1.0 mmol) and 3,5-dimethyl phenyl boronic acid 2 (1.2 mmol) were used as reagents for Pd-catalyzed homocoupling reactions. With these reagents, the homocoupling product 4 was obtained in 70% yield exclusively under conditions with Pd2(dba)3.CHCl3 (0.025 mmol), rac-BINAP (0.05 mmol) and Cs2CO3 (1.5 mmol) in dioxane (5 mL). When KF was used to replace Cs2CO3, an improved yield of the homocoupling product (97%) was obtained. With an xcex1-bromo ketone 5, 6 and a homocoupling product 4 were obtained (Scheme 2).
To explore the scope of this reaction, the examination of several aryl boronic substrates and other xcex1-bromo carbonyl compounds were investigated (Table 1). Using ethyl xcex1-bromo acetate ester 7, both homocoupling and crosscoupling products were observed (Table 1, entries 1, 3-5, 7, 9 and 12). Interestingly, substitution at the xcex1-position of xcex1-bromo carbonyl compounds (e.g., 1) promotes the homocoupling reaction and inhibits the crosscoupling reaction (Table 1, entries 3 and 5). Furthermore, addition of water influences the selectivity between homocoupling and crosscoupling products in this system. For example, in the presence of water, the ratio of homocoupling and crosscoupling product switched from 30:70 to 70:30 in the coupling reaction of ortho-methyl phenyl boronic acid and ethyl xcex1-bromide acetate ester (Table 1, entries 3 and 4). When the reaction was carried out using an xcex1-substituted bromocarbonyl compound in the presence of water, only homocoupling products were observed for many substrates, i.e., target compounds (Table 1, entries 2, 6, 8, and 10-17). It is noteworthy that this novel homocoupling coupling reaction appears to tolerate a variety of functional groups, e g., aldehyde, methoxy, nitro groups, etc. The presence of an ortho-methoxyl group in aryl boronic acids also gave high yields of the homocoupling product (see, e.g., different selectivities in entries 3, 12 and 14).
To explain the experimental results, possible reaction mechanisms are illustrated in Scheme 3. In the first step, the reaction is initiated by oxidative addition of an xcex1-bromocarbonyl compound to a Pd(0) species to form compound 8. Intermediate 9 is formed after the first transmetallation and isomerization of 9 generates a palladium enolate intermediate 10, which undergoes a second transmetallation to yield the intermediate 12. Reductive elimination of 12 produces the homocoupling product 4. On the other hand, the reductive elimination of 9 gives the crosscoupling product 3. It is believed that isomerization of 9 to 10 and transmetallation of 10 with the aryl boronic acid 2 are reversible. The homocoupling path (Sp2xe2x80x94Sp2 coupling) is preferred when reductive elimination of 9 is inhibited using an xcex1-substituted bromocarbonyl compound as a reagent (reductive elimination barrier of Sp2-Sp3 coupling is increased in the presence of a bulky Sp3 group). In addition, presence of water will hydrolyse 11 and drive the reaction toward the intermediate 12. As the result, the homocoupling reaction is promoted. 
By employing a similar approach, homocoupling of many acetylenes under the mild conditions can be achieved. The transformation is illustrated below. The mild condition and high yield of this Spxe2x80x94Sp coupling is suitable to from polymers and oligomers. The reaction can tolerate a variety of functional groups. An advantage is that the reaction can be carried out under an inert atmosphere, as opposed to an oxidative environment.
For example, it is expected that HCxe2x89xa1CH may polymerize to form Sp-carbon polymers, which can be converted as an useful material for its conducting properties. Since high molecular weight polymer has not be prepared, this materials may have unexpected properties. Using YCxe2x89xa1CH as the stopping agent, an oligomer such as YCxe2x89xa1C(Cxe2x89xa1CCxe2x89xa1C)nCxe2x89xa1CY or YCxe2x89xa1C(Cxe2x89xa1C)mCxe2x89xa1CY can be formed in the condensation polymerization. The Y capping group can be SiMe3, COOR, CN, aryl, substituted aryl, alkyl and substituted alkyl. Another possibility is to make HCxe2x89xa1CZCxe2x89xa1CH first, where Z is a bridge species. The bridge can be an aryl, substituted aryl, alkyl, substituted alkyl, heteroaryl species. Polymerization of this monomer will lead to interesting materials. Where this description is only outlined few chances of application of this new reaction, the potential application is broad for making materials for may applications. The art of modem acetyline chemistry will teach the practice of this chemistry in many key transformations [Diederich, F.; Stang, P. J. Metal-catalyzed Cross-coupling Reaction, Wiley-VCH, 1998]. 
Among the more challenging problems of metal-catalyzed coupling is the Sp3xe2x80x94Sp3 coupling reactions (both intramolecular and intermolecular cases). Especially, the reaction has to tolerate beta H in both ends. By practicing an embodiment of the invention, coupling of a variety of alkynes has been achieved leading to the possibility of a variety of new polyalkynes. Especially, hydroboration of alkenes with 9-BBN or HB(OR)2 or asymmetric hydroboration of bis-alkenes will generate bis boron species. Coupling of these bis boron species can lead to formation up to four chiral centers. This strategy is very powerful for making many biologically active compounds. The hydroboration and coupling reaction is a significant method for forming a ring structure. 
While the examples provided above relate to forming Cxe2x80x94C bonds, it is conceivable that C-heteroatom bond forming reaction and some oxidation reaction can be performed using an alpha halo carbonyl compound as the oxidate. Because that metal-enolate and metal-halide has a different ability to do transmetallation and other transformation, we envision that several new reactions are possible. 